AcipHex Sprinkle

This section provides information on the proper use of a number of products that contain rabeprazole. It may not be specific to Aciphex Sprinkle. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a Medication Guide. Read and follow the instructions carefully. Ask your doctor or pharmacist if you have any questions.

Swallow the delayed-release tablet whole. Do not crush, chew, or split the tablet. You may take this medicine with or without food. If your doctor tells you to take the medicine with food, follow those instructions.

For children using the delayed-release capsules:

• Do not swallow the capsule whole.
• Take the capsule 30 minutes before a meal.
• Open the capsule and pour the contents on a small amount of soft food (eg, applesauce, fruit or vegetable baby food, yogurt) or in a small amount of liquid (eg, infant formula, apple juice, or pediatric electrolyte solution (Pedialyte®).
• Take the mixture within 15 minutes. Swallow the mixture without chewing. Do not save it for later use.

If you are taking this medicine to treat an ulcer associated with an infection, take it together with the antibiotics (eg, amoxicillin, clarithromycin) at the same time of day.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (delayed-release tablets):
  • To treat duodenal ulcers:
    • Adults—20 milligrams (mg) once a day after the morning meal.
    • Children—Use and dose must be determined by your doctor.
  • To treat duodenal ulcers with H. pylori infection:
    • Adults—20 milligrams (mg) taken with a meal 2 times a day for 7 days. The dose is usually taken together with clarithromycin and amoxicillin.
    • Children—Use and dose must be determined by your doctor.
  • To treat gastroesophageal reflux disease (GERD):
    • Adults—20 milligrams (mg) once a day.
    • Children 12 years of age and older—20 mg once a day.
    • Children younger than 12 years—Use is not recommended.
  • To prevent gastroesophageal reflux disease (GERD):
    • Adults—20 milligrams (mg) once a day.
    • Children—Use and dose must be determined by your doctor.
  • To treat Zollinger-Ellison syndrome:
    • Adults—At first, 60 milligrams (mg) once a day. Your doctor may adjust your dose if needed.
    • Children—Use and dose must be determined by your doctor.
• For oral dosage form (delayed-release capsules):
  • To treat gastroesophageal reflux disease (GERD):
    • Children 1 to 11 years and weighing 15 kilograms (kg) or more—10 milligrams (mg) once a day.
    • Children 1 to 11 years and weighing less than 15 kg—5 mg once a day. Your doctor may adjust your dose as needed.
    • Children younger than 1 year—Use is not recommended.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

The active ingredient in Aciphex Sprinkle delayed-release capsules is rabeprazole sodium, which is a proton pump inhibitor. It is a substituted benzimidazole known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]-methyl]sulfinyl]-1H–benzimidazole sodium salt. It has an empirical formula of C18H20N3NaO3S and a molecular weight of 381.42. Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform, and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions. The structural figure is:

Figure 1

Aciphex Sprinkle is available for oral administration as 5 mg and 10 mg rabeprazole sodium delayed-release capsules containing enteric coated granules.

Aciphex Sprinkle contains granules of rabeprazole sodium in a hard hypromellose capsule. Inactive ingredients are colloidal silicon dioxide, diacetylated monoglycerides, ethylcellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium oxide, magnesium stearate, mannitol, talc, titanium dioxide, carrageenan, potassium chloride, FD&C Blue No. 2 Aluminum Lake (in the 5 mg capsule), FD&C Yellow, No. 6 (in the 10 mg capsule), and gray printing ink.

Mechanism of Action

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.

In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

Pharmacokinetics

Absorption

After oral administration to healthy adults of 10 mg Aciphex Sprinkle (delayed-release capsules opened and granules sprinkled on one tablespoon [15 mL] of applesauce) under fasting condition, median time (Tmax) to peak plasma concentrations (Cmax) of rabeprazole was 2.5 hours and ranged 1.0 to 6.5 hours. The plasma half-life of rabeprazole ranges from 1 to 2 hours.

In healthy adults, a concomitant high fat meal delayed the absorption of rabeprazole from Aciphex Sprinkle (granules sprinkled on one tablespoon (15 mL) of applesauce) resulting in the median Tmax of 4.5 hours and decreased the Cmax and AUClast on average by 55% and 33%, respectively [see Dosage and Administration (2.2)].

When 10 mg Aciphex Sprinkle (granules) administered under fasting conditions to healthy adults on one tablespoon (15 mL) of applesauce, one tablespoon (15 mL) of yogurt, or when mixed with a small amount (5 mL) of liquid infant formula; the type of soft food did not significantly affect Tmax, Cmax and AUC of rabeprazole.

Distribution

Rabeprazole is 96.3% bound to human plasma proteins.

Elimination

Metabolism: Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.

Excretion: Following a single 20 mg oral dose of 14C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.

Specific Populations

Pediatric Patients: In patients with GERD 1 to 11 years of age, following once daily administration of Aciphex Sprinkle at doses from 0.14 to 1 mg/kg, the median time to peak plasma concentration ranged from 2 to 4 hours and the half-life was about 2.5 hours. No appreciable accumulation was noted following 5 days of dosing compared to exposure after a single dose.

Based on population pharmacokinetic analysis, over the body weight range from 7 to 77 kg, the apparent rabeprazole clearance increased from 8.0 to 13.5 L/hr, an increase of 69%.

The mean estimated total exposure i.e., AUC after a 10 mg dose of Aciphex Sprinkle in patients with GERD 1 to 11 years of age is comparable to AUC after 10 mg rabeprazole sodium delayed-release tablet in adults.

Male and Female Patients and Racial or Ethnic Groups: In analyses of adult data adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC0-∞ values for healthy Japanese men were approximately 50 to 60% greater than values derived from pooled data from healthy men in the United States.

Patients with Renal Impairment: In 10 adult patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance ≤5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after administration of rabeprazole 20 mg delayed-release tablets when compared to 10 healthy adult subjects.

Patients with Hepatic Impairment: In a single dose study of 10 adult patients with chronic mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a 20 mg dose of rabeprazole sodium delayed-release tablets, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy adult men.

In a multiple dose study of 12 adult patients with mild to moderate hepatic impairment administered 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, AUC0-∞ and Cmax values increased approximately 20% compared to values in healthy age- and gender-matched subjects. These increases were not statistically significant.

No information exists on rabeprazole disposition in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Effects of Other Drugs on Rabeprazole

Antacids: Co-administration of rabeprazole sodium delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

Effects of Rabeprazole on Other Drugs

Studies in healthy adult subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as theophylline (CYP1A2) given as single oral doses, diazepam (CYP2C9 and CYP3A4) as a single intravenous dose, and phenytoin (CYP2C9 and CYP2C19) given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.

Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy adult subjects including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with 20 mg rabeprazole sodium delayed-release tablets (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when rabeprazole sodium delayed-release tablets was co-administered compared to administration of clopidogrel with placebo [see Drug Interactions (7)].

Digoxin: In healthy adult subjects (n=16), co-administration of 20 mg rabeprazole sodium delayed-release tablets with 2.5 mg once daily doses of digoxin at steady state resulted in approximately 29% and 19% increase in mean Cmax and AUC(0-24) of digoxin [see Drug Interactions (7)].

Ketoconazole: In healthy adult subjects (n=19), co-administration of 20 mg rabeprazole sodium delayed-release tablets at steady state with a single 400 mg oral dose ketoconazole resulted in approximately an average of 31% reduction in both Cmax and AUC(0-inf) of ketoconazole [see Drug Interactions (7)].

Cyclosporine: In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of ACIPHEX delayed-release tablets. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

Pharmacogenomics

In a clinical study in Japan evaluating rabeprazole sodium delayed-release tablets in Japanese adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. The clinical relevance of this is not known. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.

The use of Aciphex Sprinkle in pediatric patients 1 to 11 years of age is supported by a two-part, multicenter, randomized, double-blind, parallel 2 dose arms clinical trial which was conducted in 127 pediatric patients with endoscopic and histologic evidence of GERD prior to study treatment.

Part 1 of the trial was 12 weeks in duration. Patients were randomized to one of two rabeprazole dose levels based on body weight. Patients weighing 6 to 14.9 kg received either 5 or 10 mg Aciphex Sprinkle, and those with body weight ≥15 kg received 10 mg Aciphex Sprinkle. Part 2 was a 24-week double-blinded extension of Part 1 (on same dose assigned in Part 1). Endoscopic evaluations were performed at 12 weeks (Part 1) and 36 weeks (Part 2) to assess esophageal healing. No prespecified formal hypothesis testing was conducted.

For Part 1, rates of endoscopic healing were calculated and are shown in Table 3.

Of the 87 patients with healing in Part 1, 64 patients were enrolled into Part 2. The absence of a placebo group does not allow assessment of sustained efficacy through 36 weeks. Of the 52 patients with available data, healing was observed in 47 (90%) patients at 36 weeks.

The recommended dosage of Aciphex Sprinkle is 5 mg once daily for 12 weeks in patients less than 15 kg with the option to increase to 10 mg once daily if there is an inadequate response. In patients 15 kg or greater, the recommended dosage is 10 mg once daily for 12 weeks.

NDC 13551-210-01

Rx only

AcipHex® Sprinkle™
(rabeprazole sodium)
Delayed-Release Capsules

10 mg

30 capsules

Avadel

NDC 13551-205-01

Rx only

AcipHex® Sprinkle™
(rabeprazole sodium)
Delayed-Release Capsules

5 mg

30 capsules

FSC Laboratories

Before you taking Aciphex Sprinkle, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• have any liver problems
• have any allergies
• are pregnant or planning to become pregnant
• are breastfeeding

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements.

Take Aciphex Sprinkle exactly as prescribed.

• Do not change your dose or stop taking Aciphex Sprinkle unless you talk to your doctor. Take Aciphex Sprinkle for as long as it is prescribed even if you feel better.
• Continue to take this medication for as long as it is prescribed, even if you feel better.
• Aciphex Sprinkle is usually taken once a day.
• Your doctor will tell you the time of day to take Aciphex Sprinkle.

Aciphex Sprinkle delayed release capsules:

• Take the dose 30 minutes before a meal.
• Open the capsule and sprinkle the contents onto a small amount of soft food such as applesauce, fruit ,or vegetable based baby food, or yogurt. You may also empty the capsule contents into a small amount of infant formula, apple juice, or a pediatric electrolyte solution such as Pedialyte. The food or liquid that you use should be at or below room temperature.
• Swallow the entire mixture. Do not chew or crush the granules.
• Take the entire dose within 15 minutes. If you cannot take the dose within 15 minutes of preparing it, throw it away and prepare a new dose. Do not save it for use later.

If you miss a dose of Aciphex Sprinkle, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your normal schedule. Do not take 2 doses at the same time.

Take Aciphex Sprinkle exactly as prescribed by your doctor. Follow the directions on your prescription label carefully. Your doctor will determine the right dose for you based on your medical condition.

Adults:

• The recommended dose for Aciphex Sprinkle is 20 mg once daily for 4 to 8 weeks for adults.

Children:

• The recommended dose of Aciphex Sprinkle in ages 1 to 11 who weigh more than 15 kg, is 10 mg daily for up to 12 weeks.  
• The recommended dose of Aciphex Sprinkle in children ages 1 to 11 years weighing less than 15 kg, is 5 mg per day for up to 12 weeks. Your doctor will tell you how long to take Aciphex Sprinkle.

Pregnancy category: C

Lactation: Unknown whether rabeprazole is distributed into breast milk; use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.